For the first time, scientists have shown that specific changes in cell membrane voltage and ion flow are a key determinant in whether an organism regenerates a head or a tail. Biologists at Tufts University's School of Arts and Sciences were able to control the shape of tissue regenerated by amputated planarian (flatworm) segments by manipulating the natural electrical signals that determine head-tail identity in the worms.
The research, led by Tufts Professor of Biology Michael Levin, Ph.D., is reported in the Jan. 28, 2011, issue of the journal Chemistry & Biology, appearing online Jan. 27.
"This study has uncovered a previously unknown role for bioelectric signals in patterning tissues in flatworms, an important model system for understanding the basic mechanisms of regeneration," said Susan Haynes, Ph.D., who manages Levin's and other developmental biology grants at the National Institutes of Health. "The findings suggest that control of ion channels by pharmacological agents could be a useful approach in developing regenerative therapies for tissues and organs lost to injury or disease."
The Tufts study provides critical insights into how an injured organism determines that it has deviated from normal patterning and how it then restores the missing parts--providing precisely the amount and type of tissue necessary and avoiding overgrowth or cancer.
"Our and others' previous research indicated that it is possible to trigger the process of regeneration by bioelectric means, but no one had yet shown that it is possible to actually determine what part regenerates by targeted changes in the function of ion channel and pump proteins that control transmembrane voltage potential," said Levin. "Once we understand this more fully, we hope to be able to induce human bodies to do the same."
Co-authors with Levin on the paper were three members of his laboratory: Wendy Scott Beane, Ph.D., post doctoral associate; Junji Morokuma, Ph.D., research associate; and Dany Spencer Adams, Ph.D., research associate professor.
Chemical Genetics Importantly, the work demonstrates a technique for manipulating membrane voltage during regeneration that does not rely on gene therapy.
Such a drug-based "chemical genetics" approach avoids the need to regulate each signaling pathway and epigenetic mechanism individually and circumvents the difficulties of transgenes.
Flatworms have a complex central nervous system, a true brain and a well-defined adult stem cell population. They share a significant number of genes with vertebrates. The adult worms have remarkable powers of regeneration: any piece that is cut off will regrow, including the brain.
Two Heads Better than One?
The Tufts biologists had previously identified a possible role for the enzyme H,K-ATPase and cell-cell junctions in planarian regeneration. In the recent Chemistry and Biology paper, they report that H,K,-ATPase mediates ion transport to depolarize wounded tissue and enable planaria to regenerate heads.
Further, when the biologists used ivermectin independently of H,K,-ATPase to effect depolarization, the planarian fragments also regenerated new heads. This was true even for posterior wounds, which would normally regrow tails. The induction of the same tissue pattern by completely different means that have in common only their control of membrane voltage underscores the crucial nature of voltage gradient as a physiological parameter controlling regeneration.
The biologists also reported that treatment of wounded tissue with the H,K-ATPase inhibitor SCH 28080 for 72 hours hyperpolarized the tissue and stopped head regeneration.
The researchers concluded that pharmacologically induced changes in membrane voltage are enough to trigger an entire morphogenetic program -- head regeneration -- downstream of stem cell proliferation, and serve as a master regulator of a complex patterning cascade.
Unique Research Focus
Developmental biologists commonly study biochemical signals that cells exchange during the orchestration of the tissue regeneration process. The Levin lab is unique in focusing on an important and different kind of signal: a bioelectrical language that integrates the new cells' activity with the host to enable them to establish pattern during embryogenesis, fill in missing pieces during regeneration, and avoid the shape derangement observed in cancer throughout the lifespan.
Research funding was provided by the National Institutes of Health and the National Highway Traffic Safety Administration.
"A Chemical Genetics Approach Reveals H,K-ATPase-Mediated Membrane Voltage is Required for Planarian Head Regeneration," Chemistry & Biology, Jan. 28, 2011, Wendy Scott Beane; Junji Morokuma; Dany Spencer Adams; Michael Levin.
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